September 20, 2019
13 min read

When Autoimmune Disease Strikes Thrice: Managing Multiple Autoimmune Syndrome

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Lilly Stairs

By the time Lilly Stairs was diagnosed with psoriatic arthritis at the age of 19 — following an arduous series of tests and doctor visits — she had already been living with an autoimmune disease for 12 years.

Diagnosed with psoriasis at age 7, Stairs was no stranger to the amorphous nature of autoimmune disease, including its penchant for misdiagnosis, generally unknown causes and the litany of failed therapies before reaching an effective regimen. However, Stairs does not recall being told that one autoimmune disease increases the risk of developing others — an oversight brought into focus when she was diagnosed with Crohn’s disease 6 months after her PsA diagnosis.

Stairs, now the head of client relations at Savvy Cooperative and a board member for the American Autoimmune Related Disease Association, discussed her frustrations in an interview with Healio Rheumatology.

“When I was first diagnosed with psoriatic arthritis, I saw several rheumatologists to get second and third opinions,” she said. “Not one specialist suggested I could have anything other than psoriatic arthritis — and within 6 months, I was diagnosed with Crohn’s disease. Truthfully, no one really knows if I have psoriasis, psoriatic arthritis and Crohn’s disease, or if I just have psoriasis and Crohn’s disease, because arthritis can be a symptom of both.”

The NIH estimates that at least 23.5 million people in the U.S. are affected by autoimmune disease — each of whom bears an increased risk for second (or third) autoimmune disease.
Source: Adobe Stock

One of the most surprising aspects of Stairs’ situation is that the clinicians she saw were in Boston, one of the world’s top medical hubs. “Not one doctor mentioned the possibility of another condition or walked through symptoms I was experiencing outside of my arthritis,” she said.

Just Outside the Spotlight

Stairs’ story is not as uncommon as some might think. According to NIH estimates, at least 23.5 million people in the U.S. are affected by autoimmune disease — and accompanying this growing prevalence of autoimmune disease comes an increased risk for polyautoimmunity. In their 2010 study, Cojocaru and colleagues outlined factors involved in multiple autoimmune syndrome (MAS), which they defined as the existence of three or more of these conditions.

“Disorders of autoimmune pathogenesis occur with increased frequency in patients with a history of another autoimmune disease,” they wrote, suggesting the rate of a second disorder may be approximately 25%. “At least one of them is usually a skin disease, such as psoriasis or scleroderma.”

According to Cojocaru and colleagues, multiple autoimmune disorder may be the result of familial or genetic factors, along with immunological or psychological factors. However, environmental triggers may set in motion the occurrence of a second disorder, and could be the key culprit in the rising prevalence of MAS.


“We are seeing an increased prevalence and incidence of multiple autoimmune syndrome, due in part to improved diagnostic methods,” Regina Berkovich, MD, PhD, a neurologist in Los Angeles, said in an interview. “Another reason is that providers are ordering and paying closer attention to newer laboratory information. Compared to decades ago when undiagnosed and untreated autoimmune disease frequently lead to earlier death, today, people with existing autoimmune conditions are being timely diagnosed and receiving appropriate care for it, and are living longer lives, which ironically provides them with additional time and opportunity to develop a subsequent disorder.”

Regina Berkovich

Although the most prevalent examples of MAS have been found in endocrinology with polyglandular syndromes — with patients with type 1 diabetes and celiac disease at increased risk for polyautoimmunity — evidence of MAS have been noted in autoimmune systemic rheumatologic diseases as well as gastrointestinal, dermatologic and neurological disorders.

Patients with rheumatoid arthritis, multiple sclerosis, autoimmune thyroiditis, Sjögren’s syndrome, inflammatory bowel disease and psoriatic diseases all carry a substantially increased risk for another autoimmune disease, as do rarer conditions such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and Graves’ disease. The potential combinations continue to multiply, making them almost impossible to track or predict.

Without guidelines for managing MAS, the physician can often be left as bewildered as the patient — many physicians, including rheumatologists, are not even aware that MAS exists. Thus, these patients volley between their neurologist, their endocrinologist and their rheumatologist, often misdiagnosed, receiving conflicting information and conflicting treatment regimens. In the absence of dedicated treatment recommendations or a physician qualified to quarterback the care of an individual with MAS, patients like Stairs must enter the clinic armed with knowledge backed by what little data are available.

Diabetes and Beyond

At the moment, much of the data emerging on MAS and other forms of polyautoimmunity are simply identifying patient populations and common combinations of disorders. Bao and colleagues examined 1,212 adults with type 1 diabetes to determine the prevalence of systemic rheumatic disease. Their results showed an age-dependent relationship between type 1 diabetes and systemic rheumatic disease among women, with 9.2% of women overall and 14% of women older than 50 years experiencing this outcome.

“As an endocrinologist, I treat many patients with type 1 diabetes, thyroid disease, adrenal insufficiency, celiac disease and pernicious anemia,” Janet B. McGill, MD, professor of medicine in the division of endocrinology, metabolism, and lipid research at Washington University School of Medicine in St. Louis, told Healio Rheumatology in an interview. “Many of these disorders coexist in the same patient, especially in those with type 1 diabetes.”

Janet B. McGill

As patients age, they may acquire additional autoimmune diseases, a reality that is more common in women, according to McGill. “For example, Hashimoto’s hypothyroidism is present in about 3% of the population but in up to 30% of those with type 1 diabetes, producing the most common combination of autoimmune diseases,” she said.

McGill also noted that when other autoimmune diseases coexist with type 1 diabetes, management of the diabetes may be more difficult, as is the case with Addison’s disease, celiac disease, IBD or the systemic rheumatic diseases, which may require treatment with steroids or immunosuppressive agents.

“Celiac and pernicious anemia may cause anemia, gastrointestinal symptoms and nutritional deficiencies, which complicate nutrition management of type 1 diabetes and other chronic illnesses,” McGill continued. “Immune deficiency disorders with pre-disposition to infection can also complicate management of type 1 diabetes and other inflammatory conditions.”

End-organ dysfunction, including kidney disease, can be a manifestation of rheumatologic conditions and a long-term complication of diabetes. “Treatments for late-stage kidney disease, whether dialysis or transplantation, complicate management of other coexisting chronic diseases,” McGill said.

Looking beyond associations with diabetes, Rojas-Villarraga and colleagues studied 1,083 patients from four autoimmune disease cohorts in a 2012 paper. They found that 34.4% of the study population exhibited polyautoimmunity, with autoimmune thyroid disease and Sjögren’s syndrome the most frequently implicated diseases.

“In my patient population, which is primarily MS, evidence of other autoimmune conditions is quite high,” Berkovich said. “We see Sjögren’s syndrome, myelitis and different types of vasculitis, just to name a few of them. “We are diagnosing more and more patients with different combinations of autoimmune conditions. I pay very close attention to them as those factors present valuable information on a patient’s immune phenotype and serve me as a good clinical biomarker.”

It is for this reason that patients like one identified by Samanta and colleagues may become more prevalent. They presented a case report of a 15-year-old girl with Aicardi-Goutières syndrome due to compound heterozygous pathogenic variants who developed vitiligo, alopecia areata, immune thrombocytopenia, and positive antithyroglobulin antibodies without positive antinuclear antibody or features of systemic lupus erythematosus.

Genetics and Other Suspects

There is little doubt that genetic factors are at play in these patients. However, the challenges in pinpointing the genetic culprit of one disease are significant enough — to do so in a patient with three complicated diseases seems insurmountable.


Cortes and Zeron conducted a literature review to identify the genes with the most involvement in the development of thyroid pathologies. Their results showed that activation of oncogenes such as RAS, BRAF, RET/PTC and the overstimulation of the PI3K/AKT pathway were significant in thyroid tumorigenesis, while SLC5A5, SLC26A4, TG, TPO, DUOX2, and DUOXA2 were associated with hypothyroidism. Other findings showed associations between Graves' disease and HLA-DR3, CTLA4, PTPN22, CD40, IL2RA (CD25), FCRL3 and IL23R. FOXE1 may relate to hypothyroidism and papillary thyroid cancer. They concluded that thyroid diseases are “polygenetic,” with no gene specifically causal in pathogenesis.

Chaim Putterman

“There are many examples in animal studies where a particular gene is knocked out, and it results in a disease phenotype,” Chaim Putterman, MD, chief of the division of rheumatology at the Albert Einstein College of Medicine and Montefiore Medical Center, told Healio Rheumatology. “But if you knock out that gene in a different mouse strain, or genetic background, you get a different disease, or a different magnitude or type of disease.”

Putterman highlighted PTPN22 in humans as an example of the importance of interactions with background genes in determining the actual effects of a gene of interest. “In one individual, PTPN22 can be a risk factor for one autoimmune disease, but in another individual,that same gene is a risk factor for another, quite distinct autoimmune disease,” he said. “There are too many possibilities for interacting genes that modify expression resulting in a wide variety of phenotypes in any given individual.”

Investigators like Schmidt and colleagues are trying to understand all of these possibilities, as established in their comprehensive review of primary immunodeficiency syndromes along with their pathogenetic mechanisms and relationship to autoimmune diseases. “Increased understanding of the complex immune regulatory and signaling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases,” they wrote. “Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms.”

“More and more, we are seeing patients with different diseases who have shared susceptibility,” Putterman said. “Meaning, a gene associated with one condition can lead to susceptibility to other autoimmune conditions as well”

Despite these advances in genetic understanding of MAS, Daniel G. Arkfeld, MD, professor of clinical medicine at the Keck School of Medicine at the University of Southern California, still believes the research community is far from being able to predict who is likely to develop multiple conditions. “Nothing is 100% yet, or even close to it,” he said, highlighting another important point for the rheumatologists to consider. “Environmental factors and triggers are a major issue that we need to be examining alongside genetic information.”

Daniel G. Arkfeld

As an example, Arkfeld pointed out high rates of RA discordance among twins. “We have to ask ourselves why the same genetic sequences would not evolve into the same problem,” he said.

Putterman also believes that encouraging patients to manage environmental factors can be beneficial in the clinic. “There should be a strong emphasis on medications, toxins and infections that predispose patients to autoimmune disease,” he said. “The genetic contribution to pathogenesis in these patients is much smaller than the environmental contributions.”

Treatment Pitfalls

Even after these patients have been identified, and their three or more autoimmune conditions have been correctly diagnosed, treating them presents a whole new set of challenges.

“When you treat one condition, you may improve a comorbid condition, but you also might predispose the patient to the development of another condition,” Berkovich said. For example, she noted that patients with MS undergoing continuous treatment with interferons can develop autoimmune thyroiditis, and that treatment with alemtuzumab (Campath, Genzyme) may predispose some patients to other autoimmune conditions.

Similarly, treatment of psoriasis with a TNF inhibitor may trigger demyelinating condition like MS, according to Berkovich, who added that patients with both MS and psoriasis should not be treated with interferons. “The presence of another autoimmune condition in an MS patient may indicate IL-17 or other type of pathological immunology,” she said.

The minefield continues. McGill said that patients with celiac disease, pernicious anemia or IBD may not absorb thyroid hormones normally and may require unusually high doses. “Likewise, individuals with hypoparathyroidism may find it difficult to take thyroid hormones and sufficient calcium,” she said.

Patients with diabetes who are treated with steroids will have difficulty with fluctuating insulin requirements, while those who require immunosuppressive agents may be at risk for infections that complicate diabetes management, according to McGill. “Disease manifestations such as difficulty swallowing and kidney or vision problems complicate management of any chronic disease,” she said. “Other therapeutic pitfalls relate to the cost of care of these complex patients, which can be substantial.”

In the biologic era, rheumatologists have grown accustomed to reaching some level of personalized medicine in treating their patients, according to Putterman. But MAS patients are considerably more complicated and difficult to treat than a patient who has only lupus or RA. “What is important is early recognition,” he said. “The more prompt you are in initiating a treatment regimen, the better the long-term outcomes are likely to be.”


A bit of good news is that rheumatologists have become accustomed to complex treatment regimens. “We find ourselves going down a rabbit hole of sometimes using five or 10 drugs in our patients,” Arkfeld said. “This may be beneficial in managing MAS.”

Berkovich added that prompt treatment does more than just mitigate symptoms of the disease states. “Starting earlier can make a huge difference in getting patients to live their lives and keep their jobs,” she said.

But finding the adequate regimen for one patient at a time is a far cry from having reliable treatment algorithms to work from, so each clinician is left to figure things out on their own. It is tedious, time consuming, and often marked by more failure than success.

Managing Patients Across Specialties

With so many challenges in diagnosis and treatment, and with patients who are often treated by three or more specialists, it should go without saying that doctor-patient and doctor-doctor communication is critical.

But reminders are always helpful, particularly when patients can present as though they are “between conditions,” according to Berkovich. “Patients with multiple autoimmune syndrome can fit the criteria for many different conditions, even ones they do not have,” she said. “We are hoping to continuously improve diagnostic criteria to optimize their sensitivity and specificity, so that the ‘gray area’ or ‘mysterious diagnosis’ problem disappears, but we are not quite there yet.”

When living with multiple autoimmune diseases, coordinating care across specialists often results in a high administrative burden on the patient, Stairs told Healio Rheumatology. “A particularly frustrating concern is that some physicians refuse to coordinate with other specialists outside of their own care facility,” she said.

Arkfeld argued that rheumatologists are used to dealing with complex patients and coordinating with other specialties. “But it is important to understand that general practitioners and other specialists may not be as familiar with the conditions involved or the drugs we use,” he said.

In Europe, to address these issues of potential miscommunication as well as hypersegmented and uncoordinated care, there is movement toward creating a specialist called an autoimmunologist. “This expert is someone who can cross specialties and focus on autoimmunity,” Putterman said. “Instead of a dermatologist seeing a patient with vitiligo, a rheumatologist seeing a patient with lupus, and an endocrinologist seeing a patient with diabetes, you can have someone who is focusing on the common mechanisms underlying all of these diseases.”


With one physician who understands the fundamental mechanisms, improved and timely treatment decisions are likely to follow. But that is not a reality in the U.S. In the absence of an autoimmunologist, Putterman suggested that shared infusion centers can help bring specialists together with patients. “We have opened an infusion center where rheumatology, nephrology, endocrinology and other specialties meet,” he said. “This is an opportunity for shared patient management. It is a start.”

These centers are few and far between, though, meaning patients often face delays in diagnosis of a second or third condition, according to McGill. “It is all too common for a patient with type 1 diabetes who complains of fatigue and aching to have these complaints mistakenly attributed to her diabetes,” she said. “In reality, she was developing early rheumatoid arthritis.”

Coordination of care has become easier with electronic medical records, but the time and expense incurred by patients is still significant, McGill added. “Often treatments need to be coordinated, for example, when a person with diabetes requires steroids or when the doses of steroids change,” she said.

Patient perspective

Stairs expounded on how patients can fend for themselves amid treatment by an unrelated team of doctors. “To help mitigate the administrative burden placed on patients, one recommendation is to pick one specialist, or primary care physician when possible, to ‘own’ the patient case,” she said.

Her next recommendation was to coordinate appointments for the same day whenever possible. “It is also useful to implement combined care clinics,” she said. “For example, a center in which dermatologists and rheumatologists can see complex patients on the same day in the same office.”

Most of all, Stairs said to give patients access to a direct line of communication about all aspects of their care. “This does not need to be the specialist,” she said. “Administrators or nurses can be great in this capacity, as well.”

Patients like Stairs understand that specialists are often double- and triple-booked and are given a short window of time to see patients. “With that in mind, I also recommend asking patients what administrative burdens they are facing,” she said. “Sometimes, physicians can step in to help ease the burden.”

She offered an example from her own patient experience. “I was on a subcutaneous biologic and regularly traveled into my specialists’ office to be administered the medication,” she said. “I encountered administrative hurdle after hurdle: from the office staff not understanding that I had to be scheduled every 8 weeks to avoid falling out of remission to long wait times and students that would come in before the physician to ask a laundry list of questions, all for an injection which took less than a minute from box open to band-aid.”


Only after she voiced her frustration, she was told that the appointment could be scheduled with a nurse instead of a physician. “With this simple change, 90% of the administrative burden was lifted,” she said.

Zeroing back in on clinical approaches to MAS, Stairs suggested viewing patients holistically. “Last year, I gave the keynote presentation at the Interdisciplinary Autoimmune Summit,” she said. “In preparation, I collected the thoughts of fellow patient advocates on their experience coordinating care across physicians and working with specialists. One of the most poignant responses came from Hay Farris who remarked:

“My main complaint? Specialists treating my body as separate pieces based on their training and not as a whole system where everything affects everything else. I am not just a messed-up liver. I am not just a vascular disease. I am a complex mixture of those.” – by Rob Volansky


  • Anaya JM, et al. Clin Rev Allergy Immunol. 2012;doi: 10.1007/s12016-012-8317-z.
  • Bao YK, et al. J Diabetes Complications. 2018;doi: 10.1016/j.jdiacomp.2018.06.001.
  • Cojocaru M, et al. Maedica (Buchar). 2010;5:132-134.
  • Cortes JMR, Zeron HM. Folia Med (Plovdiv). 2019;doi: 10.2478/folmed-2018-0078.
  • Rojas-Villarraga A, et al. Autoimmune Dis. 2012;doi:10.1155/2012/254319
  • Samanta D, et al. Pediatr Neurol. 2019;doi: 10.1016/j.pediatrneurol.2019.01.017.
  • Schmidt RE, et al. Nat Rev Rheumatol. 2017;doi:10.1038/nrrheum.2017.198.

For more information:

  • Daniel Arkfeld, MD, can be reached at 2020 Zonal Ave # 620, Los Angeles, CA 90089; email:
  • Regina Berkovich, MD, PhD, can be reached at 8727 Beverly Boulevard Ste B Ste B, West Hollywood, CA 90048; email:
  • Janet McGill, MD, can be reached at 4921 Parkview Pl Floor: 13, Suite: B, St. Louis, MO 63110; email:
  • Chaim Putterman, MD, can be reached at 1300 Morris Park Ave, Bronx, NY 10461; email:
  • Lilly Stairs can be reached at

Disclosure: Arkfeld, McGill and Putterman report no relevant financial disclosures. Berkovich reports consulting for Alexion, Bayer, Biogen, Celgene, Genentech, Mallinckrodt, Novartis, and Sanofi. Stairs reports being a patient consultant/advisor to Clara Health, Janssen and ZappRx, and noted having pharma clients through work at Savvy Cooperative.